Opioids Opioid Compound with morphinelike activity Opiate Substance

Opioids

• Opioid – Compound with morphine-like activity • Opiate – Substance extracted from opium – Exudate of unripe seed capsule of Papaver somniferum – Contain 2 types of alkaloids Phenanthrene derivatives • Morphine (10% in opium) • Codeine (0. 5% in opium) • Thebaine (0. 2% in opium), (Nonanalgesic) Benzoisoquinoline derivatives • Papaverine (1%) Nonana. Igeslic • Noscapine (6%)

Opioids • Mordern definition of opioid – Molecule that interact with opioid receptor • Opioid compound – Opioid receptor agoninsts, antagonists, agonists-antagonists – Natural products, synthetic and semisynthetic compounds – peptides synthesized by neurone and other cell

CLASSIFICATION OF OPIOIDS Natural opium alkaloids: • Morphine • Codeine Semisynthetic opiates: • Diacetylmorphine (Heroin) • Pholcodeine Synthetic opioids: • Pethidine (Meperidine) • Fentanyl, Alfentanil, Sufentanil, Remifentanil • Methadone • Dextropropoxyphene • Tramadol

COMPLEX ACTION OPIOIDS AND OPIOID ANTAGONISTS Agonist-antagonists ( analgesics) • Nalorphine • Pentazocine • Butorphanol Partial/weak agonist + antagonist • Buprenorphine Pure antagonists • Naloxone • Naltrexone • Nalmefene

Pain Pathophysiology • Pain is an ill-defined, unpleasant sensation, evoked by an external or internal noxious stimulus. • Analgesic relieves pain without significantly altering consciousness. • Pain perception has 2 components – Nociceptive component – Affective component

Pain pathway & Sites of action of opioids • Pain pathways (ascending & descending) • Ascending pain pathway- Starts from terminals of primary afferent neurons fibres eg. – A - fast conducting – C - slow conducting

Sites of action on the afferent pain transmission pathway from the periphery to the higher.

• Descending pathway exert inhibitory effect on pain transmission through Substantia Gelatinosa (SG) • Sensory Aβ fibres (arising from peripheral tissues) stimulate release of met-enkephlin from interneurons of SG and block pain transmission • So massaging, rubbing, acupunture, counter-irritants provide pain relief • Morphine inhibit release of glutamate from primary afferent fibres in the spinal cord • Gate control mechanism

Opioid analgesic action on the descending inhibitory pathway

Brainstem local circuitry underlying the modulating effect of -opioid receptor (MOR)

• Brainstem local circuitry underlying the modulating effect of -opioid receptor (MOR)– mediated analgesia on descending pathways. • The pain-inhibitory neuron is indirectly activated by opioids (exogenous or endogenous), which inhibit an inhibitory (GABAergic) interneuron. • This results in enhanced inhibition of nociceptive processing in the dorsal horn of the spinal cord

Opioid Receptor Transducer Mechanism • Agonist binding -conformational changes in the GPCR -Inhibition of adenylyl cyclase activity ( , ) -Stimulation of K+ current ( , ) -Inhibition of voltage-gated Ca 2+ channels ( ) -decreased release of neurotransmitter (substance-P, neurokinin A, neurokinin B, glutamate)

• Most of available opioid analgesics – Act at -opioid receptor • Activation of -opioid receptor → analgesia, euphoria, respiratory depress, nausea, vomiting, decreased gastrointestinal motility, tolerance, dependence • -, -opioid receptor – – analgesia dysphoria, Psychotomimetic ( ) Affective behaviour, proconvulsant ( ) Not cause respiratory depression or to decease GI motility → Analgesia without -opioid side effect

• antagonist- β-funaltrexamine • antagonist-Norbinaltorphimine • antagonist- Naltrindole

• Morphine – , , receptor activation • Fentanyl, sufentanyl – More selective -receptor agonist – High effective analgesia

Endogenous Opioid Peptides • A number of endogenous opioid peptides having morphine like activity are found in brain, pituitary, spinal cord, GIT • • • β-Endorphins - Enkephalins - & Dynorphins- Endomorphins- Nociceptin- NOP receptor (nociceptin opioid peptide receptor)

Effects of Morphine Central Nervous System Effects Analgesia • Pain consists of both sensory and affective (emotional) components. • Opioid analgesics reduce both aspects of the pain experience, especially the affective aspect. • In contrast, nonsteroidal anti-inflammatory analgesic drugs have no significant effect on the emotional aspects of pain. Euphoria • intravenous drug users experience a pleasant floating sensation with lessened anxiety and distress (DA release in nucleus accumbance). • However, dysphoria, an unpleasant state characterized by restlessness and malaise, may sometimes occur.

Sedation • • • Drowsiness clouding of mentation little or no amnesia No motor incoordination Sleep is induced in the elderly (can be easily aroused from this sleep)

Respiratory Depression • by inhibiting brainstem respiratory mechanisms. • Alveolar PCO 2 may increase, but the most reliable indicator of this depression is a depressed response to a carbon dioxide challenge. • In individuals with increased intracranial pressure, asthma, chronic obstructive pulmonary disease, or cor pulmonale, this decrease in respiratory function may not be tolerated.

Cough Suppression • Codeine in particular • However, cough suppression by opioids may allow accumulation of secretions and thus lead to airway obstruction and atelectasis. Temperature regulating centre depression • chances of hypothermia Vasomotor centre depression • Fall in BP

Morphine stimulates: • CTZ (nausea, vomiting) • Edinger Westphal nucleus of III nerve is stimulated (miosis) • Vagal centre (bradycardia)

Miosis • Constriction of the pupils • By stimulating Edinger Westphal nucleus of III nerve • Miosis is a pharmacologic action to which little or no tolerance develops • valuable in the diagnosis of opioid overdose.

Truncal Rigidity • Truncal rigidity reduces thoracic compliance and thus interferes with ventilation. • Truncal rigidity may be overcome by administration of an opioid antagonist, which of course will also antagonize the analgesic action of the opioid. • Preventing truncal rigidity while preserving analgesia requires the concomitant use of neuromuscular blocking agents.

Peripheral Effects Cardiovascular System • Bradycardia Meperidine is an exception (can result in tachycardia) • Hypotension - due to -peripheral arterial and venous dilation -depression of vasomotor centre -release of histamine. • Increased PCO 2 leads to cerebral vasodilation associated with a decrease in cerebral vascular resistance, an increase in cerebral blood flow, and an increase in intracranial pressure.

Gastrointestinal Tract Constipation • no tolerance • Opioid receptors exist in high density in the gastrointestinal tract • constipating effects of the opioids are mediated through an action on the enteric nervous system as well as the CNS • gastric secretion of hydrochloric acid is decreased • propulsive peristaltic waves are diminished • tone is increased • this delays passage of the fecal mass and allows increased absorption of water, which leads to constipation • so used in the management of diarrhea

Biliary Tract • sphincter of Oddi may constrict • contract biliary smooth muscle • result in biliary colic Renal • Renal function is depressed by opioids • decreased renal plasma flow • enhanced renal tubular sodium reabsorption • Ureteral and bladder tone are increased • Increased sphincter tone may precipitate urinary retention • ureteral colic caused by a renal calculus is made worse by opioid-induced increase in ureteral tone

Uterus • may prolong labor • both peripheral and central actions of the opioids can reduce uterine tone Neuroendocrine • stimulate the release of ADH, prolactin, and somatotropin • inhibit the release of luteinizing hormone Pruritus • CNS effects and peripheral histamine release may be responsible for these reactions • pruritus and occasionally urticaria (when administered parenterally)

Miscellaneous The opioids modulate the immune system by • lymphocyte proliferation • antibody production • chemotaxis

Clinical Use of Opioid Analgesics • • Analgesia Cough Diarrhea Acute Pulmonary Edema Balanced anaesthesia Preanaesthetic medication Relief of anxiety and apprehension

Toxicity & Undesired Effects

Acute morphine poisoning • >50 mg of morphine • Lethal dose is 250 mg • Stupor, coma, shallow breathing, cyanosis, pinpoint pupil, fall in BP, convulsions • Death due to respiratory failure Treatment • Positive pressure respiration • Iv fluids • Gastric lavage with potassium permagnate • Naloxone

Tolerance and Dependence • With frequently repeated therapeutic doses of morphine, there is a gradual loss in effectiveness • To reproduce the original response, a larger dose must be administered • Along with tolerance, physical dependence develops • Physical dependence is defined as a characteristic withdrawal or abstinence syndrome when a drug is stopped or an antagonist is administered

Tolerance and Dependence • Maintenance of normal sensitivity of receptors requires reactivation by endocytosis and recycling. • activation of receptors by endogenous ligands results in endocytosis followed by resensitization and recycling of the receptor to the plasma membrane. • But morphine fails to induce endocytosis of the -opioid receptor - tolerance and dependence. • In contrast, methadone, used for the treatment of opioid tolerance and dependence, does induce receptor endocytosis.

Tolerance and Dependence • NMDA receptor ion channel complex play a critical role in tolerance development and maintenance • NMDA-receptor antagonists such as ketamine can block tolerance development

Withdrawal is manifested by significant somatomotor and autonomic outflow- • • • agitation hyperalgesia hyperthermia hypertension diarrhea pupillary dilation • release of all pituitary and adrenomedullary hormones • affective symptoms -dysphoria -anxiety -depression These phenomena are highly aversive and motivate the drug recipient to make robust efforts to avoid the withdrawal state

Contraindications and Cautions in Therapy Use of Pure Agonists with Weak Partial Agonists • morphine with pentazocine - risk of diminishing analgesia or even inducing a state of withdrawal Use in Patients with Head Injuries • Carbon dioxide retention caused by respiratory depression results in cerebral vasodilation. • In patients with elevated intracranial pressure, this may lead to lethal alterations in brain function. • Marked respi. depression • Vomiting, miosis, altered mentation by morphine interferes with assessment of pt condition

Use during Pregnancy • In pregnant women who are chronically using opioids, the fetus may become physically dependent in utero and manifest withdrawal symptoms in the early postpartum period. • A daily dose as small as 6 mg of heroin (or equivalent) taken by the mother can result in a mild withdrawal syndrome in the infant, and twice that much may result in severe signs and symptoms, including irritability, shrill crying, diarrhea, or even seizures. • When withdrawal symptoms are mild - diazepam • with more severe withdrawal - methadone

Use in Patients with Impaired Pulmonary Function • opioid analgesics may lead to acute respiratory failure. Use in Patients with Impaired Hepatic or Renal Function • morphine and its congeners are metabolized primarily in the liver • Half-life is prolonged in patients with impaired renal function Use in Patients with Endocrine Disease -adrenal insufficiency (Addison's disease) and hypothyroidism (myxedema) – -prolonged and exaggerated responses to opioids.

Related drugs Pethidine • 1/10 th in analgesic potency • Spasmodic action on smooth muscles is less • Tachycardia (antimuscarinic action)- it is related to atropine, even acts on opioid receptors • Safer in asthmatics (less histamine release) • Uses- analgesia, preanaesthetic medication • Preferred opioid analgesic during labour (less neonatal respi depression)

Fentanyl 80 -100 times more potent than morphine few cardiovascular effects little propensity to release histamine. Because of high lipid solubility, it enters brain rapidly and produces peak analgesia in 5 min after i. v. injection. • The duration of action is short: starts wearing off after 30 -40 min due to redistribution • Transdermal fentanyl has become available for use in cancer • •

Methadone • Slow & persistant action • Sedative & subjective effects are less intense • No kick • Less abuse potential • Use- as substitute therapy for opioid dependence • 1 mg methadone for 4 mg morphine.

Tramadol – Analgesic action mechanism • Weak affinity for -opioid receptor • norepinephrine & 5 -HT reuptake Inhibition – Advantage • Less respiratory depression, nausea, vomiting, constipation • Less abuse potential • Rapid psychomotor recovery – Labour pain, injury, surgery (other short lasting pain) – Moderate pain treatment : as effective as morphine – Severe pain treatment : less effective than morphine

Pentazocine ( analgesic) • It has agonistic actions and weak opioid antagonistic activity • elicit dysphoric and psychotomimetic effects • increase in blood pressure and heart rate Uses- • moderate to severe pain • as a preoperative medication and • as a supplement to anesthesia

Buprenorphine (weak agonist & antagonist) • 25 -50 times more potent than morphine • Sublingual route • Slower onset & longer duration of action • Postural hypotension is marked • Cannot be used during labour (respi dep not reversed by naloxone) Uses • Long lasting pain- cancer • Tt of morphine dependence

Naloxone ( , , antagonist) • Antagonizes all morphine actions • Sedation is less completely reversed • Blocks placebo, acupuncture, stress induced analgesia Use • Morphine poisoning • Diagnostic test for opioid addiction • Revert neonatal respi depression due to opioid use during labour

Peripherally Acting Opioid • Opioid receptor – outside central nerve system – Peripherally acting opioid agonist → analgesia without CNS side effect • Loperamide, Diphenoxylate – – -opioid receptor agonist Not cross blood-brain barrier Treatment : inflammation-induced hyperalgesia Relieve diarrhea • Alvimopan – peri -opioid receptor antagonist – Relieves constipation in opium addicts – Without precipitating opioid withdrawl – Treat postoperative paralytic ileus

Opioid with Other Analgesics • Goal of using analgesics in combination – Achieve superior analgesia – Reduce dose of each drug – Minimizing side effect • NSAID – Synergistical action with systemic opioid to produce analgesia • Local anesthetics and opioid – Synergistical pain relief when intrathecal or epidural administration

MCQs Q 1. Which of the following actions is ascribed to kappa type of opioid receptors? • Euphoria • Proconvulsant • Dysphoria • Muscular rigidity • Ans- C

Q 2. In epidural analgesia morphine acts by acting on • Ventral horn • Substantia gelatinosa • Sensory nerve • Axons • Ans- B

Q 3. Which of the following opioid is more potent than morphine? • Tramadol • Fentanyl • Pethidine • Codeine • Ans- B

Q 4. Which is NOT a feature of opioid withdrawal? • constipation • piloerection • yawning • Rhinorrhoea • Ans- A

Q 5. Pentazocine acts as a: • weak antagonist and partial agonist at opioid receptors • antgonist at opioid receptors • inverse agonist at opioid receptors • agonist at opioid receptors • Ans- A

Thank you

Bibliography • Essentials of Medical Pharmacology -7 th edition by KD Tripathi • Goodman & Gilman's the Pharmacological Basis of Therapeutics 12 th edition by Laurence Brunton (Editor) • Lippincott's Illustrated Reviews: Pharmacology - 6 th edition by Richard A. Harvey • Basic and Clinical pharmacology 11 th edition by Bertram G Katzung • Rang & Dale's Pharmacology -7 th edition by Humphrey P. Rang • Clinical Pharmacology 11 th edition By Bennett and Brown, Churchill Livingstone • Principles of Pharmacology 2 nd edition by HL Sharma and KK Sharma • Review of Pharmacology by Gobind Sparsh